Palladium-catalyzed through-space C(sp3)-H and C(sp 2)-H bond activation by 1,4-palladium migration: Efficient synthesis of [3,4]-fused oxindoles

Article abstract of DOI:10.1002/anie.201306532

Palladium two step: Linear anilides were converted into the title compounds in good to excellent yields through a palladium-catalyzed domino carbopalladation/1,4-palladium shift sequence. The C(sp³)-H activation involves a seven-membered pallad

Full text of DOI:10.1002/anie.201306532

Angewandte
Chemie
DOI: 10.1002/anie.201306532
Synthetic Methods
3
2
À
À
Palladium-Catalyzed Through-Space C(sp ) H and C(sp ) H Bond
Activation by 1,4-Palladium Migration: Efficient Synthesis of [3,4]-
Fused Oxindoles**
Tiffany Piou, Ala Bunescu, Qian Wang, Luc Neuville, and Jieping Zhu*
Oxindoles are highly valuable synthetic targets because of
their presence in numerous natural products, pharmaceuti-
cals, and agrochemicals.[1] Although a plethora of strategies
has been developed for the synthesis of spirooxindoles,
methods allowing rapid access to the no less important
[3,4]-fused oxindoles[2] remain scarce.[3] Transition-metal-
À
catalyzed C H functionalization has emerged recently as
a powerful tool for the synthesis of heterocycles.[4] Despite
recent major advancements, palladium-catalyzed functional-
3
À
ization of non-activated C(sp ) H bonds is still an important
challenge.[5–8] In continuation of our current research on the
À
development of domino processes incorporating a C H
3
functionalization,[9] and more specifically a C(sp ) H activa-
À
tion step,[10] we became interested in the transformation of the
anilides 1 into the [3,4]-fused oxindoles 2. The underlying
principle is shown in Scheme 1. Oxidative addition of 1 to
palladium(0) and subsequent intramolecular carbopallada-
tion gives the s-alkyl/PdII intermediate A. This palladium
Scheme 1. Synthesis of [3,4]-fused oxindoles by a domino carbopalla-
3
species is ideally positioned to activate the neighboring
À
dation/1,4-palladium migration/C(sp ) H activation sequence. For the
2
À
aromatic C(sp ) H bond, thus leading to the five-membered
sake of simplicity, a hypothetical concerted metalation–deprotonation
(CMD) mechanism[5f] was drawn for C H activation steps. Ligands on
palladium were omitted for clarity.
À
palladacycle B. A formal proton transfer from B results in
a net 1,4-palladium shift[11] from the alkyl to the aryl
II
position.[12,13] The so generated Pd /aryl species C, after C
À
C bond rotation, is expected to activate the neighboring C4
methyl group to furnish the seven-membered palladacycle D.
Reductive elimination finally affords the tetracyclic oxindole
2 with concurrent regeneration of the palladium(0) species.
To realize this projected domino process, several chal-
lenges needed to be addressed: a) Finding reaction conditions
to accommodate every elementary step could be a dilemma.
Indeed from the perspective of ligand selection, it is known
that bidentate phosphine ligands are generally preferred for
migration processes,[14] whereas electron-rich and bulky
3
À
monodentate phosphine ligands are ideal for C(sp ) H
activation.[6] b) Very few examples of six-membered-ring
3
À
À
formation by C(sp ) H activation/C C bond formation are
known.[15] c) Formation of the benzocyclobutane[16] from B
instead of palladium migration might also be a competitive
side reaction.
Keeping these considerations in mind, reaction conditions
were surveyed using the easily accessible N-(2-bromo-3-
methylphenyl)-N-methyl-2-phenylacrylamide (1a-Br) as
a test substrate.[17] After an extensive survey of reaction
conditions (see the Supporting Information), a combination
of Pd(OAc)2, PCy3·HBF4, and CsOPiv[18] in DMA was found
to be effective, thus affording 2a in 55% yield (Table 1,
entry 3). Importantly, we found that the yield of 2a increased
significantly when a tertiary amine was introduced as an
additive (entries 6–9), with N,N-diethylaniline being the best.
Under the optimum reaction conditions found, the [3,4]-fused
oxindole 2a was isolated in 84% yield (entry 8).[19] Interest-
ingly, a chloroanilide (1a-Cl) was a competent substrate to
afford 2a in 65% yield (entry 10). Conversely, a iodoanilide
(1a-I) was a bad substrate, thus producing the desired product
2a in only 13% yield (entry 11).
[*] Dr. T. Piou, A. Bunescu, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Dr. L. Neuville
Centre de Recherche de Gif, Laboratoire International Associꢀ
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
[**] Financial support from the EPFL (Switzerland), Swiss National
Science Foundation (SNF), Swiss National Centres of Competence
in research (NCCR), and ICSN, CNRS (France) are gratefully
acknowledged. T.P. thanks ICSN and EPFL for a doctoral fellowship.
A.B. thanks EPFL for a doctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306532.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Reaction optimization.[a]
(2b–e) in excellent yields. In these cases, the carbopalladation
and the subsequent domino process was apparently faster
2
À
than the alternative direct aromatic C(sp ) H functionaliza-
tion as the competitive formation of phenanthridine and
carbazole was not observed in these cases.[20] Electron-
donating and electron-withdrawing groups located ortho,
meta, or para to the nitrogen atom were all well tolerated (2 f–
h). However, an attempt to prepare 2i by activation of
a methylene group failed.
The influence of the substitution on the a-aryl unit
(ring B) was next investigated (Scheme 3). Substituents at the
para position, regardless of their electronic nature (methyl,
phenyl, methoxy, and fluoro), exerted a marginal effect on the
Entry
Ligand
Base(s)
X
Yield [%][b]
1
2
3
4
5
6
7
8
dppm
PPh3
CsOPiv
CsOPiv
CsOPiv
Cs2CO3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
n.d.[c]
53
55
trace
trace
75
63
84
51
65
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
[d]
CsOPiv/Cs2CO3
[d]
CsOPiv/N(nBu)3
CsOPiv/PMP[d]
[d]
CsOPiv/PhNEt2
CsOPiv/DBU[d]
CsOPiv/PhNEt2
CsOPiv/PhNEt2
9
10
11
[d]
[d]
13
[a] Reactions were carried out under an argon atmosphere in DMA,
c=0.1m. [b] Yield of isolated product. [c] Low conversion. [d] 1:1 ratio.
Bu=butyl, Cy=cyclohexyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DMA=N,N-dimethylacetamide, dppm=bis(diphenylphosphino)me-
thane, OAc=acetate, Ph=phenyl, Piv=pivalate, PMP=pentamethyl-
piperidine; n.d.=not determined.
With these optimized reaction conditions in hand [Pd-
(OAc)2 (0.1 equiv), PCy3·HBF4 (0.2 equiv), CsOPiv
(2.0 equiv), and N,N-diethylaniline (2.0 equiv) in DMA at
1408C], the scope of the domino process was investigated.
The structural variants on the aniline (ring A) were examined
first (Scheme 2). The use of a tertiary amide was proven to be
essential to ensure the occurrence of the domino process and
double cyclization of N-benzyl, N-para-methoxybenzyl, N-
phenyl, and N-2-(trimethylsilyl)ethoxy)methyl anilides took
place without event to provide the corresponding oxindoles
Scheme 3. Reaction scope: varying the a-aryl unit (ring B). [a] Standard
reaction conditions are detailed in Scheme 2. Yields are those for the
isolated product. [b] Only the major regioisomer is represented. The
1
ratio was determined by H NMR analysis of the crude reaction
mixture. [c] Used 0.2 equiv of Pd(OAc)2.
outcome of the reaction and provided tetracyclic [3,4]-fused
oxindoles (2j–m) in excellent yields. Two regioisomers could
be produced in the case of meta-substituted substrates.
However, regioselectivity was found to be substituent-
dependant. With a meta-methyl substituent, the cyclization
occurred preferentially at the less hindered position to afford
2n in excellent yield and regioselectivity (2n/2n’ = 92:8).
Similarly, the b-naphthal-substituted substrate afforded 2o as
a major product. In contrast, with substrates having a meta-
oxygen substituent, the regioselectivity changed, thus leading
to the more hindered tetracyclic compound 2p as the major
product (2p/2p’ = 95:5). The increased acidity of the ortho
Scheme 2. Reaction scope: varying the aniline unit (ring A). [a] Pd-
(OAc)2 (0.1 equiv), PCy3·HBF4 (0.2 equiv), CsOPiv (2.0 equiv), N,N-
diethylaniline (2.0 equiv) in DMA at 1408C. Yields are those for the
isolated product. PMB=para-methoxybenzyl, SEM=2-(trimethylsilyl)-
ethoxy]methyl.
2
À
C(sp ) H in conjunction with the chelating effect of the
oxygen atom could account for the change in regioselectivity.
The 3,5-difluorophenyl substrate was compatible with the
reaction conditions and afforded 2q in 83% yield. However,
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
substitution at ortho-position is detrimental to the reaction
(2r), most probably because of the steric hindrance.
To further explore the generality of the present domino
process, the a,b-disubstituted acrylamide derivative 1s was
submitted to our standard reaction conditions (Scheme 4).
À
Scheme 5. Direct C H activation prevailed over 1,4-palladium migra-
tion. [a] Standard reaction conditions as detailed in Scheme 2. Yields
are those for the isolated product.
were subjected to the standard reaction conditions
(Scheme 6). These results clearly indicated that both 1,4-
3
À
palladium migration and C(sp ) H activation were reversi-
ble.[23] The partial deuterium loss can be explained by proton
exchange between palladium(II) intermediates (B and D,
3
2
À
À
Scheme 4. Chemoselective activation of C(sp ) H over C(sp ) H: syn-
thesis of 3-benzyl substituted [3,4]-fused oxindoles. [a] Standard reac-
tion conditions are detailed in Scheme 2. Yields are those for the
isolated product.
Scheme 6. Isotope-labeling experiments. [a] Standard reaction condi-
tions as detailed in Scheme 2.
Mechanistically, the intermediate E, generated by intramo-
lecular carbopalladation and 1,4-palladium migration, could
Scheme 1) and the reaction media. These observations made
the kinetic studies very difficult and inconclusive (for addi-
tional kinetic isotope effect studies, see the Supporting
Information).[24]
3
À
activate either the neighboring C4 methyl C(sp ) H (path a)
2
À
or the aromatic C(sp ) H (path b), thus leading to the
formation of the [3,4]-fused tetracycle 2s and spirooxindole
3, respectively. In both cases seven-membered palladacycles
(F and G) are formed. Interestingly, 2s was formed exclu-
In conclusion, we developed a novel palladium(0)-cata-
2
À
lyzed carbopalladation/1,4-palladium shift by a C(sp ) H
3
À
À
sively (80%) at the expense of 3. These results are surprising
bond activation/C(sp ) H bond activation/C C bond-form-
ing process. The C(sp ) H activation went through a rare
2
3
À
À
since activation of C(sp ) H bonds (path b) are generally
3
[21]
À
favored over C(sp ) H bonds (path a).
This unusual
seven-membered palladacycle intermediate which occurred
2
À
chemoselectivity pattern turned out to be general under our
reaction conditions. As shown in Scheme 4, [3,4]-fused tetra-
cycles (2t–x) were formed exclusively from the corresponding
anilides regardless of the electronic property of the substitu-
ent in the aromatic ring (ring C).
chemoselectively in the presence of a competitive C(sp ) H
bond. The reaction allows an efficient synthesis of tetracyclic
[3,4]-fused oxindoles in high yields from simple starting
materials. Preliminary mechanistic studies demonstrated the
3
À
reversibility of both the 1,4-palladium migration and C(sp )
However, when substrates allowed the reaction going
through a six-membered palladacycle intermediate, reductive
elimination prevailed over the alternative 1,4-palladium
migration process. As shown in Scheme 5, 1y and 1z were
converted into the corresponding spirocycles 4 and 5 by
H activation processes under the reaction conditions.
Experimental Section
N-(2-Bromo-3-methylphenyl)-N-methyl-2-phenylacrylamide (1a-Br;
20.0 mg, 0.061 mmol, 1.0 equiv) was charged into a tube equipped
with a stirring bar and was introduced into a nitrogen filled glovebox.
Pd(OAc)2 (1.4 mg, 0.006 mmol, 0.1 equiv), PCy3·HBF4 (4.5 mg,
2
3
[22]
À
À
C(sp ) H and C(sp ) H bond activations, respectively.
Significant deuterium loss and deuterium scrambling were
observed when the deuterated substrates [D2]-1a and [D3]-1a
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
0.012 mmol, 0.2 equiv), and CsOPiv (28.7 mg, 0.122 mmol, 2.0 equiv)
were added, followed by degassed N,N-dimethylacetamide (1.6 mL,
c = 0.1m) and N,N-diethylaniline (20.0 mL, 0.122 mmol, 2.0 equiv).
The resulting mixture was stirred for 3 min at room temperature and
then overnight in a preheated oil bath at 1408C. The reaction mixture
was partitioned between ethyl acetate and aqueous HCl solution
(1.0n). The aqueous layer was extracted with ethyl acetate and the
combined organic extracts were washed with water, aqueous NaOH
solution (1.0n), and brine, and then dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 95:5) to afford 2,10b-dimethyl-6,10b-
dihydronaphtho[1,2,3cd]indol-1(2H)-one 2a (12.7 mg, 84%).
b) J. J. Neumann, S. Rakshit, T. Drçge, F. Glorius, Angew. Chem.
2009, 121, 7024 – 7027; Angew. Chem. Int. Ed. 2009, 48, 6892 –
6895; c) M. Wasa, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010,
132, 3680 – 3681; d) E. J. Yoo, M. Wasa, J.-Q. Yu, J. Am. Chem.
Soc. 2010, 132, 17378 – 17380; e) K. J. Stowers, K. C. Fortner,
M. S. Sanford, J. Am. Chem. Soc. 2011, 133, 6541 – 6544; f) P.
Novꢂk, A. Correa, J. Gallardo-Donaire, R. Martin, Angew.
Chem. 2011, 123, 12444 – 12447; Angew. Chem. Int. Ed. 2011, 50,
12236 – 12239; g) Y. Ano, M. Tobisu, N. Chatani, J. Am. Chem.
Soc. 2011, 133, 12984 – 12986; h) G. He, G. Chen, Angew. Chem.
2011, 123, 5298 – 5302; Angew. Chem. Int. Ed. 2011, 50, 5192 –
5196; i) E. T. Nadres, O. Daugulis, J. Am. Chem. Soc. 2012, 134,
7 – 10; j) A. Iglesias, R. Alvarez, A. R. de Lera, K. MuÇiz,
Angew. Chem. 2012, 124, 2268 – 2271; Angew. Chem. Int. Ed.
Received: July 26, 2013
Revised: August 29, 2013
Published online: && &&, &&&&
2012, 51, 2225 – 2228.
[8] Enantioselective C(sp ) H functionalization. Palladium(II)-cat-
3
À
alyzed: a) B.-F. Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew.
Chem. 2008, 120, 4960 – 4964; Angew. Chem. Int. Ed. 2008, 47,
4882 – 4886; b) M. Wasa, K. M. Engle, D. W. Lin, E. J. Yoo, J.-Q.
Yu, J. Am. Chem. Soc. 2011, 133, 19598 – 19601; Palladium(0)-
catalyzed: c) M. Nakanishi, D. Katayev, C. Besnard, E. P.
Kꢃndig, Angew. Chem. 2011, 123, 7576 – 7579; Angew. Chem.
Int. Ed. 2011, 50, 7438 – 7441; d) S. Anas, A. Cordi, H. B. Kagan,
Chem. Commun. 2011, 47, 11483 – 11485; e) T. Saget, S.
Lemouzy, N. Cramer, Angew. Chem. 2012, 124, 2281 – 2285;
Angew. Chem. Int. Ed. 2012, 51, 2238 – 2242; f) D. Katayev, M.
Nakanishi, T. Bꢃrgi, E. P. Kꢃndig, Chem. Sci. 2012, 3, 1422 –
1425; g) N. Martin, C. Pierre, M. Davi, R. Jazzar, O. Baudoin,
Chem. Eur. J. 2012, 18, 4480 – 4484; For a review, see: h) R. Giri,
B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev.
2009, 38, 3242 – 3272.
À
Keywords: C H activation · chemoselectivity · heterocycles ·
palladium · synthetic methods
.
[1] Recent reviews: a) A. Millemaggi, R. J. K. Taylor, Eur. J. Org.
Chem. 2010, 4527 – 4547; b) F. Zhou, Y.-L. Liu, J. Zhou, Adv.
Synth. Catal. 2010, 352, 1381 – 1407.
[2] a) K. Stratmann, R. E. Moore, R. Bonjouklian, J. B. Deeter,
G. M. L. Patterson, S. Shaffer, C. D. Smith, T. A. Smitka, J. Am.
Chem. Soc. 1994, 116, 9935 – 9942; b) C. Kikuchi, T. Ando, T.
Watanabe, H. Nagaso, M. Okuno, T. Hiranuma, M. Koyama, J.
Med. Chem. 2002, 45, 2197 – 2206; c) M. Tsuda, T. Mugishi, K.
Komatsu, T. Sone, M. Tanaka, Y. Mikami, M. Hirai, Y. Ohzumi,
J. Kobayashi, Tetrahedron 2003, 59, 3227 – 3230.
[3] a) J. Li, N. Wang, C. Li, X. Jia, Org. Lett. 2012, 14, 4994 – 4997;
b) D. D. Schwarzer, P. J. Gritsch, T. Gaich, Angew. Chem. 2012,
124, 11682 – 11684; Angew. Chem. Int. Ed. 2012, 51, 11514 –
11516; c) S. Bhunia, S. Ghosh, D. Dey, A. Bisai, Org. Lett.
2013, 15, 2426 – 2429; [3,4]-fused cyclic indoles: d) S. P. Breaz-
zano, Y. B. Poudel, D. L. Boger, J. Am. Chem. Soc. 2013, 135,
1600 – 1606; e) D. Shan, Y. Gao, Y. Jia, Angew. Chem. 2013, 125,
5002 – 5005; Angew. Chem. Int. Ed. 2013, 52, 4902 – 4905.
[9] a) G. Cuny, M. Bois-Choussy, J. Zhu, Angew. Chem. 2003, 115,
4922 – 4925; Angew. Chem. Int. Ed. 2003, 42, 4774 – 4777; b) A.
Pinto, L. Neuville, J. Zhu, Angew. Chem. 2007, 119, 3355 – 3359;
Angew. Chem. Int. Ed. 2007, 46, 3291 – 3295; c) A. Salcedo, L.
Neuville, C. Rondot, P. Retailleau, J. Zhu, Org. Lett. 2008, 10,
857 – 860; d) T. Gerfaud, L. Neuville, J. Zhu, Angew. Chem. 2009,
121, 580 – 585; Angew. Chem. Int. Ed. 2009, 48, 572 – 577; e) A.
Pinto, L. Neuville, J. Zhu, Tetrahedron Lett. 2009, 50, 3602 –
3605; f) S. Jaegli, W. Erb, P. Retailleau, J.-P. Vors, L. Neuville,
J. Zhu, Chem. Eur. J. 2010, 16, 5863 – 5867; g) S. Jaegli, J. Dufour,
H.-L. Wei, T. Piou, X.-H. Duan, J.-P. Vors, L. Neuville, J. Zhu,
Org. Lett. 2010, 12, 4498 – 4501; h) T. Piou, L. Neuville, J. Zhu,
Org. Lett. 2012, 14, 3760 – 3763; i) T. Piou, L. Neuville, J. Zhu,
Tetrahedron 2013, 69, 4415 – 4420.
À
[4] “C H Activation”: Topics in Current Chemistry, Vol. 292 (Eds.:
J.-Q. Yu, Z.-J. Shi), Springer, Berlin, 2010.
[5] a) O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902 – 4911; b) H. Li,
À
B.-J. Li, Z.-J. Shi, Catal. Sci. Technol. 2011, 1, 191 – 206. C H
functionalization in natural product synthesis, see: c) L. McMur-
ray, F. OꢀHara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885 –
1898; d) W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011, 40,
1976 – 1991; e) D. Y.-K. Chen, S. W. Youn, Chem. Eur. J. 2012,
18, 9452 – 9474; f) D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39,
[10] T. Piou, L. Neuville, J. Zhu, Angew. Chem. 2012, 124, 11729 –
11733; Angew. Chem. Int. Ed. 2012, 51, 11561 – 11565.
[11] For reviews on palladium migration, see: a) S. Ma, Z. Gu,
Angew. Chem. 2005, 117, 7680 – 7685; Angew. Chem. Int. Ed.
2005, 44, 7512 – 7517; b) F. Shi, R. C. Larock, Top. Curr. Chem.
2010, 292, 123 – 164; c) For a recent example involving 1,7-
palladium migration, see: J. Zhou, J. He, B. Wang, W. Yang, H.
Ren, J. Am. Chem. Soc. 2011, 133, 6868 – 6870.
[12] a) R. F. Heck, J. Organomet. Chem. 1972, 37, 389 – 396; b) J.
Cꢂmpora, J. A. Lꢄpez, P. Palma, P. Valerga, E. Spillner, E.
Carmona, Angew. Chem. 1999, 111, 199 – 203; Angew. Chem. Int.
Ed. 1999, 38, 147 – 151; c) G. Karig, M.-T. Moon, N. Thasana, T.
Gallagher, Org. Lett. 2002, 4, 3115 – 3118; d) Q. Huang, A. Fazio,
G. Dai, M. A. Campo, R. C. Larock, J. Am. Chem. Soc. 2004, 126,
7460 – 7461; e) O. Renꢁ, D. Lapointe, K. Fagnou, Org. Lett. 2009,
11, 4560 – 4563; f) Z. Lu, C. Hu, J. Guo, J. Li, Y. Cui, Y. Jia, Org.
Lett. 2010, 12, 480 – 483.
1118 – 1126.
3
À
[6] Selected recent examples of palladium(0)-catalyzed C(sp ) H
activation: a) O. Baudoin, A. Herrbach, F. Gueritte, Angew.
Chem. 2003, 115, 5914 – 5918; Angew. Chem. Int. Ed. 2003, 42,
5736 – 5740; b) C.-G. Dong, Q.-S. Hu, Angew. Chem. 2006, 118,
2347 – 2350; Angew. Chem. Int. Ed. 2006, 45, 2289 – 2292; c) M.
Lafrance, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
14570 – 14571; d) T. Watanabe, S. Oishi, N. Fujii, H. Ohno, Org.
Lett. 2008, 10, 1759 – 1762; e) A. Salcedo, L. Neuville, J. Zhu, J.
Org. Chem. 2008, 73, 3600 – 3603; f) M. Wasa, K. M. Engle, J. Q.
Yu, J. Am. Chem. Soc. 2009, 131, 9886 – 9887; g) S. Rousseaux,
M. Davi, J. Sofack-Kreutzer, C. Pierre, C. E. Kefalidis, E. Clot,
K. Fagnou, O. Baudoin, J. Am. Chem. Soc. 2010, 132, 10706 –
10716; h) J. Pan, M. Su, S. L. Buchwald, Angew. Chem. 2011, 123,
8806 – 8810; Angew. Chem. Int. Ed. 2011, 50, 8647 – 8651; i) S.
[13] For reviews on the Catellani reaction, see: a) M. Catellani,
Synlett 2003, 298 – 313; b) M. Catellani, E. Motti, N. Della Caꢀ,
Acc. Chem. Res. 2008, 41, 1512 – 1522; c) A. Martins, B.
Mariampillai, M. Lautens, Top. Curr. Chem. 2010, 292, 1 – 33;
d) R. Ferraccioli, Synthesis 2013, 581 – 591.
Rousseaux, B. Liꢁgault, K. Fagnou, Chem. Sci. 2012, 3, 244 – 248.
3
À
[7] For palladium(II)-catalyzed C(sp ) H activation, see: a) B.
Liꢁgault, K. Fagnou, Organometallics 2008, 27, 4841 – 4843;
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[14] a) M. A. Campo, R. C. Larock, J. Am. Chem. Soc. 2002, 124,
14326 – 14327; b) M. A. Campo, H. Zhang, T. Yao, A. Ibdah,
R. D. McCulla, Q. Huang, J. Zhao, W. S. Jenks, R. C. Larock, J.
Am. Chem. Soc. 2007, 129, 6298 – 6307.
[15] a) G. Dyker, Angew. Chem. 1992, 104, 1079 – 1081; Angew.
Chem. Int. Ed. Engl. 1992, 31, 1023 – 1025; b) H. Ren, P.
Knochel, Angew. Chem. 2006, 118, 3541 – 3544; Angew. Chem.
Int. Ed. 2006, 45, 3462 – 3465; c) T. Saget, N. Cramer, Angew.
Chem. 2012, 124, 13014 – 13017; Angew. Chem. Int. Ed. 2012, 51,
12842 – 12845.
[20] Phenanthridine, see: a) L.-C. Campeau, M. Parisien, A. Jean, K.
Fagnou, J. Am. Chem. Soc. 2006, 128, 581 – 590; b) F. Bonnaterre,
M. Bois-Choussy, J. Zhu, Beilstein J. Org. Chem. 2008, 4, 1 – 6;
Carbazoles, see: c) D. E. Ames, D. Bull, Tetrahedron 1982, 38,
383 – 387.
[21] To the best of our knowledge, there were only two examples
reported in the literature: a) L.-C. Campeau, D. J. Schipper, K.
Fagnou, J. Am. Chem. Soc. 2008, 130, 3266 – 3267; b) C. Tsukano,
M. Okuno, Y. Takemoto, Angew. Chem. 2012, 124, 2817 – 2820;
Angew. Chem. Int. Ed. 2012, 51, 2763 – 2766.
[16] M. Chaumontet, R. Piccardi, N. Audic, J. Hitce, J.-L. Peglion, E.
Clot, O. Baudoin, J. Am. Chem. Soc. 2008, 130, 15157 – 15166.
[17] For details, see the Supporting information. The substrate 1a was
synthesized in two steps starting from the commercially available
2-bromo-3-methylaniline and 2-phenylacrylic acid.
[18] M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496 –
16497.
[22] Compounds of type 1z lacking the ortho methyl group failed to
undergo spirocyclization (Ref. [10]). We are examining this
divergency in detail.
[23] a) J. Zhao, M. A. Campo, R. C. Larock, Angew. Chem. 2005, 117,
1907 – 1909; Angew. Chem. Int. Ed. 2005, 44, 1873 – 1875; b) A.
Mota, A. Dedieu, C. Bour, J. Suffert, J. Am. Chem. Soc. 2005,
127, 7171 – 7182.
[19] Structure of 2a was confirmed by X-ray analysis. See the
Supporting information.
[24] E. M. Simmons, J. F. Hartwig, Angew. Chem. 2012, 124, 3120 –
3126; Angew. Chem. Int. Ed. 2012, 51, 3066 – 3072.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
T. Piou, A. Bunescu, Q. Wang, L. Neuville,
J. Zhu*
&&&& — &&&&
Palladium-Catalyzed Through-Space
3
2
À
À
C(sp ) H and C(sp ) H Bond Activation
by 1,4-Palladium Migration: Efficient
Synthesis of [3,4]-Fused Oxindoles
Palladium two step: Linear anilides were
converted into the title compounds in
good to excellent yields through a palla-
dium-catalyzed domino carbopallada-
tion/1,4-palladium shift sequence. The
C(sp3)-H activation involves a seven-
membered palladacycle, and is chemo-
selective in the presence of competitive
2
À
C(sp ) H bonds. DMA=N,N-dimethyl-
acetamide, OPiv=pivalate.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!